EXCEED THE SPACE PROVIDED. Apoptosis or programmed cell death contributes to neurotoxicity in numerous chronic neurodegenerative diseases. Oxidative stress is believed to be a principle factor. In Alzheimer's disease, for example, there is evidence for oxidative stress due to: 1) increased levels of aluminum, iron and mercury; 2) increased lipid peroxidation (generation of 4-hydroxynonenal); 3) reduced energy metabolism and less cytochrome c oxidase; 4) increased DNA and protein oxidation; and 5) increased generation reactive oxygen species by amyloid B (AB). Multiple transgenic models for Alzheimer's disease have been developed. Most involve the overexpression of various mutated forms of amyloid precursor protein resulting in increased AB secretion and plaque formation. The loss of neurons in these animal models, however, is conspicuously absent. Why are the neurons in the brains of these transgenic mice resistant to the effects of AB? These mice could be viewed not as a failed model for Alzheimer's disease but instead as a model for the prevention of the neuronal death associated with AB production, deposition and plaque formation. This proposal is designed to address this question in the Hsiao mice (Tg2576). Initial screens for changes in the prototypical antioxidant gene NAD(P)H:quinone oxidoreductase (NQO1) indicate that mRNA and protein for this gene are increased in Hsiao mice relative to littermate controls. Expression of NQO1 and numerous other protective genes can be increased by multiple mechanisms including oxidative stress through activation of the antioxidant response element (ARE). The observed changes in the Hsiao mice, therefore, may be due to ARE activation. Finally, pretreatment with tert-butylhydroquinone(tBHQ) decreases glutamate-, dopamine-, and H2O2- induced cytotoxicity (apoptosis) in rodent and human neuroblastoma cells. The protection afforded by tBHQ is attributed to the coordinate increase in ARE-driven genes. Cortical neuronal and astrocytic cultures fromARE- hPAP reporter mice indicate that tBHQ-mediated activation of the ARE occurs in both neurons and astrocytes. We hypothesize that increased expression of ARE-driven genes will block oxidative stress-induced cell death and contributes to the lack of neurotoxicity in the Hsiao mice. The specific aims of this proposal are: 1) To determine the effect of overexpression of amyloid precursor protein on the ARE and antioxidant genes in neurons and glia; 2) To characterize the expression pattern and induction of antioxidant genes in neurons and glia of Nrf-2 null mice and determine if the lack of Nrf2 results in increased sensitivity to oxidative stress; 3) To determine the effect of overexpression of amyloid precursor protein on antioxidant gene expression, neuronal survival and plaque formation in Nrf-2 null mice.